Severe brain hypoxia results in respiratory excitation, which takes the form of gasping. If gasps sufficiently reoxygenate the lungs and heart, cardiorespiratory function will rapidly improve; thus, survival during severe hypoxic exposures appears to be critically dependent upon gasping, which functionally promotes autoresuscitation. Although gasping is important for survival, the underlying neural mechanisms responsible for the genesis of hypoxia-induced gasping remain unclear. Recent work, including work from our laboratory, has demonstrated that the pre-Botzinger complex (pre-BotC), which is essential for the generation of normal breathing, is hypoxia chemosensitive, and therefore, may participate in the genesis of hypoxia related gasping. The mechanism(s) by which pre-BotC neurons "sense" hypoxia, leading to respiratory excitation (gasping), however, is not known. Numerous modalities have been suggested to participate in O2 sensing in other "hypoxia chemosensors", including direct effects on ion channel conductance and release of excitatory and inhibitory neurotransmitters and neuromodulators. Recent observations, for example, have suggested that K+(ATP) channels may be part of the molecular substrate for O2 detection in hypoxia-sensitive central nervous system (CNS) neurons, and that persistent sodium channels may act as O2 sensors. Although both of these types of channels are present in pre-BotC neurons, it remains to be determined whether these channels participate in the hypoxia-sensing function of this region. Recent studies have also proposed that substance P (SP) and nitric oxide (NO), both of which are released during severe brain hypoxia in some CNS regions, may play a role in the hypoxia-sensing function of the carotid body. Although neurokinin-1 (SP) receptors and NO synthase (i.e., enzyme for NO production) are expressed by pre-BotC neurons, it remains to be determined whether these neuroactive agents participate in the hypoxia-sensing function of this region. The major objective of the work proposed in this application is to investigate whether these potential mechanisms participate in the hypoxia-sensing function of the pre-BotC, and the subsequent generation of hypoxia-induced gasping. The experiments proposed in this application will use an in vivo vagotomized, deafferented, decerebrate or anesthetized adult cat model to assess the roles of K+(ATP) channels, persistent sodium channels, SP, and NO in the hypoxia-sensing function of the pre- BotC. The effects of both focal and systemic hypoxic stimuli will be examined.